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Figure44.4 Endoscopic ultrasound- guided

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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elastography from a masspancreatitis, showing the typical green heterogeneous predominant pattern.

forming chronic

Endoscopic Ultrasound- Guided Elastography 369

Figure44.5 Endoscopic ultrasound- guided elastography from a pancreatic cancer, with a heterogeneous blue predominant pattern,

showing a strain ratio of 20.27, and a strain histogram of 29.

soft (green) pattern [27]. Chronic pancreatitis can be differentiated from pancreatic cancer by a difference in the elastography appearance in most of the cases. It is important to highlight the different pattern in cases of autoimmune pancreatitis, characterized by a diffuse stiff pattern in the pancreatic parenchyma, not just in the focal mass[25,26].

Elastography can also be evaluated in a quantitative manner by calculating the ratio between the strain in the region of interest and a reference area in surrounding

soft tissue (strain ratio) or evaluating the strain histogram of the selected area. Malignant pancreatic masses and neuroendocrine tumors produce higher strain ratios and lower strain histograms than inflammatory masses and normal parenchyma. It has been suggested that a strain ratio of >10 or a mean strain histogram value of <50 is associated with malignancy[26,28,29] (Fig.44.5). Color patterns, strain ratio, and strain histogram values for the evaluation of solid pancreatic lesions are shown in Tables44.1 and44.2.

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Table44.1 Elastographic patterns classification.

Color and pattern Stiffness Malignancy

Homogeneous blue predominant

Heterogeneous blue predominant (Fig.44.3)

Heterogeneous green predominant (Fig.44.4)

Homogeneous green predominant (Fig.44.5)

Heterogeneous green and blue without predominant color

Table44.2 Elastographic values onquantitative evaluation.

Strain ratio Strain histogram Malignancy

>10 <50 Ye s

<10 >50 No

Hard Ye s

Intermediate No

Soft No

Intermediate hard

Undetermined

Different meta- analysis have evaluated the diagnostic performance of EUS elastography for the characterization of malignant pancreatic tumors. Overall, a high sensitivity (92–98%), but a low specificity (67–76%) have been reported[30,31]. No significant advantage of semiquantitative strain elastography over qualitative strain elastography has been demonstrated. The low specificity can explain the difficult interpretation of cases with chronic calcifying pancreatitis. Calcifications show a hard blue pattern, as expected, so it is important in these cases to evaluate the areas where no calcifications are present. In a recent multicenter study, 50% of solid pancreatic lesions ≤15 mm proved to be soft, and the probability of a soft lesion to be malignant was negligible[32]. Therefore, due to its very high negative predictive value for malignancy, EUS elastography may have a specific value for the evaluation of small pancreatic lesions. A topic of specific interest in the evaluation of chronic pancreatitis cases is the role of elastography to detect blue spots (hard tissue) inside the mass- forming chronic pancreatitis, to target the area of sampling. A study on 54 patients with solid pancreatic lesions, using a 25- gauge EUS needle that was inserted into the most suspicious part of the lesion according to EUS elastography (Fig.44.6), reported a positive diagnosis of carcinoma in 85% of patients. The diagnostic accuracy, sensitivity, and specificity of the combination EUS- elastography/FNA was 94%, 93%, and 100%, respectively[33].

Endoscopic Ultrasound- Guided ContrastEnhancement

Contrast enhanced harmonic EUS (CEH- EUS) is a methodology to further improve the EUS- based differential diagnosis of solid pancreatic tumors. The development of microbubble- based contrast agents together with technological advances and refinement in ultrasound technology has led to improved imaging of fine vascular structures and visualization of microflow patterns within target lesions[34,35].

Lesions of interest should be reported and documented in terms of their specific contrast enhancement by looking separately into the arterial phase and the venous phase over time. Thereby, the temporal behavior of signals can be assessed and compared with those signals arising from the surrounding tissues (nonor hyperenhancement) and with its contrast distribution (homogenous or heterogeneous). Besides qualitative descriptions, the intensity of depicted contrast signals can be quantified by the calculation of time–intensity curves both during the wash- in and wash- out phases[36]. Several parameters can be calculated for further reviews such as peak enhancement, rise time, wash- in and washout rate, area under the curve, and others.

The main contrast agent available is SonoVue/Lumason (Bracco Imaging, Milan, Italy), containing microbubbles composed of sulfur hexafluoride gas enclosed in a lipid shell. After intravenous injection, the pancreatic arterial phase occurs within 15–30 s before a venous phase starts approximately 30–45 s after injection[36].

CEH- EUS can differentiate the nature of solid pancreatic lesions, particularly pancreatic ductal adenocarcinoma that is typically hypoenhanced (Fig. 44.7). In this regard, pancreatic adenocarcinoma differs from other solid lesions such as neuroendocrine tumors, pancreatic metastases, or pseudotumoral (mass- forming) focal chronic pancreatitis. Both mass- forming chronic pancreatitis and autoimmune pancreatitis present as iso- or hyperenhanced pseudotumors as opposed to the hypoenhanced lesions associated with pancreatic adenocarcinoma. Contrast enhancement can also be used to assess therapeutic response in the treatment of autoimmune pancreatitis[35].

Several meta- analyses have shown the accuracy of this methodology in the differential diagnosis of solid pancreatic tumor, mainly for the detection of pancreatic cancer. Sensitivity ranges from 85% to 90%, and specificities from 80% to 90%[37–39]. A large multicenter trial that included 167 consecutive patients indicated that peak enhancement, wash- in area under the curve, wash- in rate, and the wash- in perfusion index were significantly different in patients with chronic pancreatitis

, hypo- , iso- ,

Figure44.6 Endoscopic ultrasound- guided

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sampling from a pancreatic solid tumor, guided by elastography (targeting the blue area of the lesion).

Endoscopic Ultrasound- Guided ContrastEnhancement 371

Figure44.7 Contrast- enhanced harmonic

endoscopic ultrasound of a pancreatic solid tumor, a pancreatic adenocarcinoma, showing the typical hypoenhanced pattern.

and pancreatic cancer[40]. Furthermore, using a model of artificial neural networks for the parameters listed above, the authors found an increased sensitivity (94%), specificity (94%), positive predictive value (97%), and negative predictive value (90%). The diagnostic yield of CEH- EUS for the diagnosis of pancreatic cancer versus other tumors in lesions <15 mm has been confirmed in a recentmulticenter trial including 219 patients, indicating

an overall 89% accuracy [41]. Recently, time–intensity curve analysis has also been used with a high diagnostic accuracy of 91% to characterize focal pancreatic lesions[42].

Contrast- enhanced EUS can also be used for targeting EUS- guided sampling. However, a recent study has shown that diagnostic rates for samples obtained using 22- gauge needles with standard EUS- guides sampling

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and CEH- EUS- guided sampling were not significantly different [43]. However, the use of CEH- EUS may reduce the number of needle passes needed to reach a diagnosis as compared to conventional techniques [44].

Combination of EUS-Guided Advanced Imaging and Tissue Sampling

The combined use of different EUS technologies has been shown to improve the diagnosis of solid pancreatic lesions. A recent meta- analysis selected 17 studies evaluating elastography, contrast enhancement, and tissue sampling for pancreatic lesions. The pooled sensitivity and specificity were for qualitative elastography respectively, 97% and 67%; for strain ratio 98% and 62%; for contrast enhancement 90% and 76%; and for tissue acquisition 84% and 96% [45]. Iglesiasshowed an overall accuracy for malignancy using elastography, CEH- EUS, their combination, and EUS- guided tissue acquisition of 98.4%, 85.5%, 91.9%, and 91.5%, respectively. Importantly, the combination of advanced imaging provided very useful information for establishing the malignant potential of the lesions[28]. Costache etal. conducted a multicenter trial on the combined use of EUS- guided elastography and CEH- EUS. Elastography

García et al.

showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 29.63%,

78.65%, 100%, and 80.41%, respectively. Corresponding values for CEH-

EUS (considering hypoenhancement as a predictive factor of malignancy) were 98.57%, 77.78%, 92%, 95.45%, and 92.78%, respectively. Combining CEHEUS (hypoenhancement) and EUS- guided elastography, the sensitivity, specificity, and accuracy were 98.57%,

81.48%, and 93.81%, respectively. Best results were obtained using a sequential clinical algorithm based on the initial use of elastography, followed by contrast enhancement[46].

Conclusions

EUS, CT, and MRI can all provide valuable and complementary information for the differential diagnosis between mass- forming chronic pancreatitis, autoimmune pancreatitis, and pancreatic adenocarcinoma. However, EUS has the unique ability to allow obtaining specimens for histopathological diagnosis safely and accurately, thus playing nowadays a crucial role in the evaluation of patients with solid pancreatic lesions. Advanced imaging (EUS- guided elastography and CEHEUS) further increase the diagnostic capabilities of EUS in this setting.

References

1 Iglesias- García J, Lindkvist B, Lariño- Noia J, Domínguez-

Muñoz JE. The role of EUS in relation to other imaging modalities in the differential diagnosis between mass forming chronic pancreatitis, autoimmune pancreatitis and ductal pancreatic adenocarcinoma. Rev Esp Enferm Dig 2012;104(6):315–321.

2 Kinney T. Evidence- based imaging of pancreatic

malignancies. Surg Clin North Am 2010;90(2):235–249.

3 Dewitt J, Devereaux BM, Lehman GA, Sherman S,

Imperiale TF. Comparison of endoscopic ultrasound and computed tomography for the preoperative evaluation of pancreatic cancer: a systematic review. Clin Gastroenterol Hepatol 2006;4(6):717–725; quiz 664.

4 Kitano M, Yoshida T, Itonaga M, Tamura T, Hatamaru K,

Yamashita Y. Impact of endoscopic ultrasonography on diagnosis of pancreatic cancer. J Gastroenterol 2019; 54(1):19–32.

5 Krishna SG, Rao BB, Ugbarugba E etal. Diagnostic

performance of endoscopic ultrasound for detection of pancreatic malignancy following an indeterminate multidetector CT scan: a systemic review and metaanalysis. Surg Endosc 2017;31(11):4558–4567.

6 Varadarajulu S, Eloubeidi MA. The role of endoscopic

ultrasonography in the evaluation of pancreaticocancer. Surg Clin North Am 2010;90(2):251–263.

7 Giovannini M. The place of endoscopic ultrasound in

bilio-

pancreatic pathology. Gastroenterol Clin Biol

2010;34(8–9):436–445.

8 Kurita Y, Kuwahara T, Hara K etal. Features of chronic

pancreatitis by endoscopic ultrasound influence the diagnostic accuracy of endoscopic ultrasound- guided fine- needle aspiration of small pancreatic lesions. Dig Endosc 2020;32(3):399–408.

9 Banafea O, Mghanga FP, Zhao J, Zhao R, Zhu L.

Endoscopic ultrasonography with fine- needle aspiration for histological diagnosis of solid pancreatic masses: a meta- analysis of diagnostic accuracy studies. BMC Gastroenterol 2016;16:108.

10 Dumonceau JM, Deprez PH, Jenssen C etal. Indications,

results, and clinical impact of endoscopic ultrasound (EUS)- guided sampling in gastroenterology: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline– updated January 2017. Endoscopy 2017; 49(7):695–714.

biliary

References 373

https://t.me/medicina_free

11 Pouw RE, Barret M, Biermann K etal. Endoscopic tissue

sampling– Part 1: Upper gastrointestinal and hepatopancreatobiliary tracts. European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 2021;53(11):1174–1188.

12 Del Vecchio Blanco G, Palmieri G, Giannarelli D etal.

Factors influencing diagnostic accuracy of endoscopic ultrasound-

guided fine- needle aspiration (EUS- FNA) in pancreatic and biliary tumors. Scand J Gastroenterol 2021;56(4):498–504.

13 van Riet PA, Erler NS, Bruno MJ, Cahen DL. Comparison

needle aspiration and fine- needle biopsy devices

of finefor endoscopic ultrasoundlesions: a systemic review and meta-

guided sampling of solid

analysis. Endoscopy

2021;53(4):411–423.

14 Crinò SF, Di Mitri R, Nguyen NQ etal. Endoscopic

ultrasoundrapid onlesions: a randomized controlled non-

guided fine- needle biopsy with or without

site evaluation for diagnosis of solid pancreatic

inferiority trial.

Gastroenterology 2021;161(3):899–909.e5.

15 Khan MA, Grimm IS, Ali B etal. A meta- analysis of

endoscopic ultrasoundendoscopic ultrasound-

fine- needle aspiration compared to

fine- needle biopsy: diagnostic yield and the value of onsite cytopathological assessment. Endosc Int Open 2017;5(5):E363–375.

16 Hartwig W, Schneider L, Diener MK, Bergmann F, Büchler

MW, Werner J. Preoperative tissue diagnosis for tumours of the pancreas. Br J Surg 2009;96(1):5–20.

17 Eloubeidi MA, Varadarajulu S, Desai S, Wilcox CM. Value

of repeat endoscopic ultrasound-

guided fine needle aspiration for suspected pancreatic cancer. J Gastroenterol Hepatol 2008;23(4):567–570.

18 Fritscher- Ravens A, Brand L, Knöfel WT etal.

Comparison of endoscopic ultrasound-

guided fine needle aspiration for focal pancreatic lesions in patients with normal parenchyma and chronic pancreatitis. Am J Gastroenterol 2002;97(11):2768–2775.

19 Varadarajulu S, Tamhane A, Eloubeidi MA. Yield of

EUS-

guided FNA of pancreatic masses in the presence or the absence of chronic pancreatitis. Gastrointest Endosc 2005;62(5):728–736; quiz 751, 753.

20 Ardengh JC, Lopes CV, Campos AD, Pereira de Lima LF,

Venco F, Módena JLP. Endoscopic ultrasound and fine needle aspiration in chronic pancreatitis: differential diagnosis between pseudotumoral masses and pancreatic cancer. JOP 2007;8(4):413–421.

21 Takahashi K, Yamao K, Okubo K etal. Differential diagnosis

of pancreatic cancer and focal pancreatitis by using EUS-

guided FNA. Gastrointest Endosc 2005;61(1):76–79.

22 Ogura T, Yamao K, Sawaki A etal. Clinical impact of K- ras

mutation analysis in EUS-

guided FNA specimens from

pancreatic masses. Gastrointest Endosc 2012;75(4):769–774.

23 Xie C, Bohy K, Abdallah MA etal. Finding a needle in

ahaystack: endoscopic ultrasound- guided fine- needle aspiration for solid pancreatic masses in the setting of

chronic pancreatitis. Ann Gastroenterol 2020; 33(4):418–425.

24 Abdallah MA, Ahmed K, Taha W etal. Endoscopic

ultrasound guided finein chronic pancreatitis: a systematic review and meta-

needle aspiration for solid lesions

analysis. Dig Dis Sci 2022;67(6):2552–2561.

25 Iglesias- García J, Lariño- Noia J, Domínguez- Muñoz JE.

New imaging techniques: endoscopic ultrasound-

guided elastography. Gastrointest Endosc Clin N Am 2017; 27(4):551–567.

26 Dietrich CF, Bibby E, Jenssen C, Saftoiu A, Iglesias- Garcia

J, Havre RF. EUS elastography: how to do it? Endosc Ultrasound 2018;7(1):20–28.

27 Iglesias- García J, Lariño- Noia J, Abdulkader I, Forteza J,

Domínguez-

Muñoz JE. EUS elastography for the characterization of solid pancreatic masses. Gastrointest Endosc 2009;70(6):1101–1108.

28 Iglesias- García J, Lindkvist B, Lariño- Noia J, Abdulkader-

Nallib I, Domínguez- Muñoz JE. Differential diagnosis of solid pancreatic masses: contrast(CEH-

EUS), quantitative- elastography (QE- EUS), or both?

enhanced harmonic

United European Gastroenterol J 2017;5(2):236–246.

29 Iglesias- García J, Lariño- Noia J, Abdulkader I, Forteza J,

Domínguez-

Muñoz JE. Quantitative endoscopic ultrasound elastography: an accurate method for the differentiation of solid pancreatic masses. Gastroenterology 2010;139(4):1172–1180.

30 Pei Q, Zou X, Zhang X, Chen M, Guo Y, Luo H. Diagnostic

value of EUS elastography in differentiation of benign and malignant solid pancreatic masses: a meta- analysis. Pancreatology 2012;12(5):402–408.

31 Zhang B, Zhu F, Li P, Yu S, Zhao Y, Li M. Endoscopic

ultrasound elastography in the diagnosis of pancreatic masses: a meta- analysis. Pancreatology 2018; 18(7):833–840.

32 Ignee A, Jenssen C, Arcidiacono PG etal. Endoscopic

ultrasound elastography of small solid pancreatic lesions: a multicenter study. Endoscopy 2018; 50(11):1071–1079.

33 Facciorusso A, Martina M, Buccino RV, Nacchiero MC,

Muscatiello N. Diagnostic accuracy of fine-

needle aspiration of solid pancreatic lesions guided by endoscopic ultrasound elastography. Ann Gastroenterol 2018; 31(4):513–518.

34 Mejuto- Fernandez R, Iglesias- García J. Contrast harmonic

endoscopic ultrasound in pancreatic diseases. Clin Endosc 2021;54(3):309–313.

35 Saftoiu A, Napoleon B, Arcidiacono PG etal. Do we need

contrast agents for EUS? Endosc Ultrasound 2020; 9(6):361–368.

36 Sidhu PS, Cantisani V, Dietrich CF etal. The EFSUMB

guidelines and recommendations for the clinical practice of contrast- enhanced ultrasound (CEUS) in non- hepatic applications: update 2017 (long version). Ultraschall Med 2018;39(2):e2–44.

Endoscopic Ultrasound forDiagnosis ofChronic Pancreatitis Versus PancreaticCancer

https://t.me/medicina_free

374

37 Gong TT, Hu DM, Zhu Q. Contrast- enhanced EUS for

differential diagnosis of pancreatic mass lesions: a meta-

analysis. Gastrointest Endosc 2012;76(2):301–309.

38 D’Onofrio M, Biagioli E, Gerardi C etal. Diagnostic

performance of contrastcontrast-

enhanced endoscopic ultrasound (ECEUS) for the

enhanced ultrasound (CEUS) and

differentiation of pancreatic lesions: a systematic review and meta-

39 Yamashita Y, Shimokawa T, Napoléon B etal. Value of

contrast-

analysis. Ultraschall Med 2014;35(6):515–521.

enhanced harmonic endoscopic ultrasonography with enhancement pattern for diagnosis of pancreatic cancer: a meta-

40 Săftoiu A, Vilmann P, Dietrich CF etal. Quantitative

contrast-

analysis. Dig Endosc 2019;31(2):125–133.

enhanced harmonic EUS in differential diagnosis of focal pancreatic masses [with videos]. Gastrointest Endosc 2015;82(1):59–69.

41 Dietrich CF, Sahai AV, D’Onofrio M etal. Differential

diagnosis of small solid pancreatic lesions. Gastrointest Endosc 2016;84(6):933–940.

42 Buxbaum J, Ko C, Varghese N etal. Qualitative and

quantitative contrast-

enhanced endoscopic ultrasound

improves evaluation of focal pancreatic lesions. Clin Gastroenterol Hepatol 2020;18(4):917–925.e4.

43 Seicean A, Samarghitan A, Bolboacă SD etal. Contrast-

enhanced harmonic versus standard endoscopic ultrasoundpancreatic lesions: a single-

guided fine- needle aspiration in solid

center prospective randomized

trial. Endoscopy 2020;52(12):1084–1090.

44 Sugimoto M, Takagi T, Hikichi T etal. Conventional

versus contrastultrasonography-

enhanced harmonic endoscopic

guided fine- needle aspiration for diagnosis of solid pancreatic lesions: a prospective randomized trial. Pancreatology 2015;15(5):538–541.

45 Lu Y, Chen L, Li C, Chen H, Chen J. Diagnostic utility of

endoscopic ultrasonographyevaluation of solid pancreatic masses: a meta-

elastography in the

analysis and

systematic review. Med Ultrason 2017;19(2):150–158.

46 Costache MI, Cazacu IM, Dietrich CF etal. Clinical

impact of strain histogram EUS elastography and contrastenhanced EUS for the differential diagnosis of focal pancreatic masses: a prospective multicentric study. Endosc Ultrasound 2020;9(2):116–121.

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Hereditary Pancreatitis andComplex Genetic Causes

Celeste Shelton Ohlsen1 and David C. Whitcomb

Ariel Precision Medicine, Pittsburgh, PA, USA

Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh/UPMC, Pittsburgh, PA, USA

1,2

375

Clinical andGenetic Definitions

Hereditary pancreatitis (HP) is a syndrome that encompasses acute pancreatitis (AP), recurrent acute pancreatitis (RAP), and chronic pancreatitis (CP). A mechanistic definition of CP is useful for framing HP as a process extending from asymptomatic risk to end- stage disease. Chronic pancreatitis is defined both by its essence and its character as “a pathologic fibro- inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathologic responses to parenchymal injury or stress”[1]. In addition, “Common features of established and advanced CP include pancreatic atrophy, fibrosis, pain syndromes, duct distortion and strictures, calcifications, pancreatic exocrine dysfunction, pancreatic endocrine dysfunction and dysplasia”[1]. The definition was designed to assist in the early diagnosis of CP, the prognosis, and in the type and timing of potential therapies.

Hereditary pancreatitis is defined by clinical presentation in a family or by genetic test results in an affected individual. In families, HP is defined as two or more firstrelatives or three or more second- degree relatives with recurrent acute pancreatitis (RAP) or chronic pancreatitis (CP) in two or more generations, consistent with an autosomal dominant inheritance pattern. Less commonly, families may appear to follow alternative inheritance patterns (e.g., autosomal recessive and complex). Alternatively, HP can be diagnosed in an individual with pancreatitis and a known pathogenic germline mutation, regardless of family history. Of importance, the penetrance of PRSS1 hereditary pancreatitis is incomplete and therefore, identification of a pathogenic PRSS1 mutation in an asymptomatic individual is not sufficient for a diagnosis but does indicate high risk. Some hereditary pancreatitis- appearing families

degree

have pathogenic variants in the serine protease inhibitor, Kazal type 1 gene (SPINK1), the cystic fibrosis transmembrane conductance regulator gene (CFTR), SPINK1 plus CFTR, the chymotrypsinogen C gene (CTRC), or a more complex genotype. Therefore, the absence of a pathogenic PRSS1 variant does not preclude the diagnosis of HP in a family. A diagnosis of HP should always be considered in idiopathic pancreatitis, early-

onset pancreatitis, or in a

family with multiple affected individuals.

Familial pancreatitis refers to the occurrence of pancreatitis of any cause in a family with an incidence greater than would be expected by chance alone. Familial pancreatitis does not follow an observable monogenic pattern of inheritance. Kindreds with familial pancreatitis may have shared genetic and/or environmental (e.g., alcohol, smoking, stress) risk factors that predispose them to pancreatitis above the general population risk.

Epidemiology

Hereditary pancreatitis is a rare genetic disorder. In 1952, Comfort and Steinburg described a large family with HP[2]. Since this initial report, hundreds of HP kindreds have been identified in several regions in the United States and Europe and in a few families in Japan, Korea, China, Thailand, Malaysia, and South America. The vast majority of HP kindreds identified in the United States are of European ancestry linked to large pedigrees (>500 people), suggesting founder effects. The reason that HP is rare in Africans and Asians is unknown.

The prevalence of hereditary pancreatitis differs by geographic region, and HP has been observed most frequently in the USA and Europe. A national series of HP in France estimated a population prevalence of at least

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Hereditary Pancreatitis andComplex Genetic Causes

100

Cumulative incidence (%)

Age of first diagnosis of feature

)

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376

0.3 per 100,000[3]. Since there is autosomal dominant inheritance with high penetrance and founders originating multiple generations in the past, the fraction of CP patients with HP will vary greatly from region to region and country to country.

Clinical Presentation

Hereditary pancreatitis typically presents with acute pancreatitis in early adolescence, with a high risk of progression to chronic pancreatitis by early adulthood (Fig.45.1). In HP, the phenotypic features are confined to the pancreas, whereas CFTR- related disorders affect multiple organs as seen in cystic fibrosis. In patients who develop CP, major comorbidities include pancreatic exocrine insufficiency, diabetes mellitus, and chronic pain syndromes. In comparison to CP of other etiologies, HP has earlier age of onset and appears to have higher cumulative risks for exocrine and endocrine failure in patients who develop chronic pancreatitis, as well as increased risk for pancreatic cancer.

The disease penetrance for a PRSS1 mutation was estimated as ~80% [4–6]. However, a national series of PRSS1- tested patients in France identified a penetrance of 93% [3]. Of note, estimates of penetrance may be inflated by biased study ascertainments. Penetrance may also differ by type of mutation and presence of modifying risk factors. Lifespan is not reduced as compared to the general population, except in patients who develop pancreatic adenocarcinoma[7].

14 years for the p.N29I mutation, and 14.5 years in patients without an identified mutation [4]. Severity, length, and frequency of attacks are variable and can vary dramatically by family. In one large kindred, 58% of PRSS1 p.R122H subjects were <5 years at the age of symptom onset[5]. Shared modifier genes and environmental factors in families contribute to age of onset and severity. For example, disease onset in four twin pairs differed by median of 1 year (range 0–2.4 years) as compared to 7 years (range 2–15 years) in a nonsibling comparison group matched for mutation, gender, and age[9].

At least 83% of patients experience epigastric abdominal pain[3]. The number of reported hospitalizations for acute pancreatitis varies by family and mutations status, with nearly 90% of affected individuals reporting >5 hospitalizations [4,5,8]. The EUROPAC study found a significant reduction in hospital admission rates for patients with a PRSS1 p.N29I mutation (0.19 per year) as compared to patients with a PRSS1 p.R122H mutation (0.33 per year)[4]. However, the difference in number of attacks between patients with an p.N29I mutation (1.4 per year) and an p.R122H mutation (2 per year) was not significantly different, suggesting that the p.N29I mutation results in less severe attacks [4]. The same study found that the majority of attacks are ≤7days in length [4], but smoldering pancreatitis and/or persistence of pain that lasts weeks or months has been reported in patients with hereditary pancreatitis[10].

Acute Pancreatitis

The median age of onset of acute pancreatitis is 10–12 years [3,4]. Some studies have shown that the age of symptom onset is earlier in PRSS1 p.R122H carriers compared to p.N29I carriers and mutation- negative patients [4,5,8]. A multicenter European (EUROPAC) study of 418 subjects from 112 families identified an age of onset of 10 years for the PRSS1 p.R122H mutation,

First symptom (AP)

Diabetes Mellitus

010203040506

Malabsorption

PDAC (a)

Chronic Pancreatitis

Recurrent acute pancreatitis progresses to chronic pancreatitis by the second or third decade of life in the majority of patients with hereditary pancreatitis. Rate and severity of pancreatic fibrosis and parenchymal destruction is highly variable, with cumulative incidence of ~50% in a lifetime (Fig.45.1). A trend exists between the number of attacks and degree of fibrosis, and this process is highly influenced by modifying factors.

Figure45.1 Age of onset of first symptoms of

acutepancreatitis, pancreatic exocrine insufficiency, pancreatic endocrine insufficiency, and pancreatic cancer (PDAC). PDAC (a) is from Ref.4 and PDAC (b) is from Ref.14 with reduced smoking. Source: Datafrom[4] and[14].

PDAC (b

Management 377

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Pancreatic Exocrine Insufficiency

Progression of inflammation and fibrosis eventually leads to pancreatic exocrine insufficiency in a significant subset of patients. Pancreatic exocrine insufficiency occurs when the pancreas cannot supply a sufficient quantity of digestive enzymes to the intestines, leading to maldigestion. The EUROPAC study identified cumulative risks for exocrine failure of 8.4% at 20 years, 37.2% at 50 years, and

60.2% at 70 years, with a median time to malabsorption of 53 years[4]. No significant difference in time to malabsorption was found between men and women[4].

Diabetes Mellitus

As with other forms of chronic pancreatitis, chronic inflammation and progressive fibrosis also lead to islet cell injury. Glucose intolerance progresses to pancreatic endocrine insufficiency from loss of insulin-

secreting beta cells. Furthermore, loss of glucagon- secreting alpha cells places patients at high risk for hypoglycemia. Diabetes mellitus from pancreatic exocrine disease and loss of all islet cell types is classified as type 3c. However, acute pancreatitis and pancreatic inflammation also triple the risk of type 2 diabetes, which develops earlier in the clinical course then type 3c[11,12]. The danger of hypoglycemia is enhanced by untreated pancreatic exocrine insufficiency, since the ingestion of nutrients is not well coordinated with digestion and absorption. The cumulative risks for endocrine failure in HP are 4.4% at 20 years, 47.6% at 50 years, and 79.1% at 80 years[4]. Median time to development of diabetes mellitus was 53 years and not significantly influenced by gender and mutation status[4].

Pancreatic Cancer

Hereditary pancreatitis is associated with a >50- fold increased risk for pancreatic adenocarcinoma [4,7,13]. Estimates for cumulative risk for pancreatic cancer at 70 years range from 7.2% to 40% [3,4,13,14]. The risk for pancreatic cancer is highest in smokers and individuals with diabetes mellitus. Smokers with HP have ~twofold increased risk for pancreatic cancer, with development of cancer 20 years earlier than nonsmokers[15]. More recent lower estimates of pancreatic cancer risk may reflect successful counseling of HP families to avoid tobacco [14]. The increased risk for pancreatic cancer appears to result from chronic inflammation rather than a PRSS1 mutation itself, since all forms of CP are associated with pancreatic cancer, but early- onset pancreatitis in HP remains one of the strongest known risk factors for pancreatic cancer.

Incidence of pancreatic cancer varies extensively

between HP families, and some families have high

incidences of pancreatic cancer in the absence of clear environmental factors, suggesting the presence of risk and/or protective variants. Annual screening for pancreatic cancer is recommended for patients with PRSS1- HP beginning at age 50 or 10 years younger than the earliest familial onset of pancreatic cancer[16].

Management

As with pancreatitis of nongenetic etiology, management is aimed at prevention, reduction of symptoms such as fibrosis, pancreatic exocrine insufficiency and pancreatic endocrine insufficiency, and alleviation of pain. The approach should be based on targeting the underlying genetic factors, minimizing environmental stressors, and considering new therapeutic interventions as indicated. Alcohol, emotional stress, and dietary fat can exacerbate pancreatitis and should be avoided. Patients should also be counseled to refrain from smoking, which doubles the already increased risk for pancreatic cancer [14,15]. Antioxidants may reduce pain in a subset of patients[17]. Common recommendations include a lowmultiple small meals a day and to maintain good hydration to reduce the risk of an attack, but these recommendations are not based on strong evidence and a normal diet is possible with appropriate pancreatic enzyme replacement therapy.

Pancreatic exocrine insufficiency should be anticipated and managed with early initiation of pancreatic enzyme replacement therapy. The diagnosis of pancreatic exocrine insufficiency currently relies on clinical suspicion from abdominal bloating, diarrhea, steatorrhea, deficiency of fat- soluble vitamins or vitamin B12, or unexplained weight loss. The most common diagnostic tests include measuring low levels of human fecal elastase, low serum trypsinogen levels, or the clinical response to a trial of pancreatic enzyme replacement therapy.

Diabetes mellitus is common both in patients with pancreatitis and in the general population. In HP, type 3c diabetes mellitus typically develops years after the onset of CP. The diagnosis is challenging, and standardized protocols are not widely accepted. However, the clinical context of advanced CP, especially with pancreatic exocrine insufficiency, should indicate caution and a multidisciplinary approach involving endocrinologists and pancreatologists. The destruction of the islets may limit the use of some antidiabetic medications, and the use of insulin must be balanced with the ingestion and digestion of the meal, which may require the addition of pancreatic enzyme replacement therapy.

In the absence of pancreatic cancer, the primary indication for surgery is pain. Total pancreatectomy with islet cell autotransplantation (TPIAT) can be

fat diet with

Hereditary Pancreatitis andComplex Genetic Causes

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considered in younger patients with intractable, narcotic- dependent pancreatic pain[18,19]. Total pancreatectomy without islet autotransplantation can be considered in older patients with chronic pancreatitis for 20 years or more to reduce pain and as a last resort to reduce the risk of developing pancreatic cancer[20,21]. The need and timing of this radical procedure requires both experience with the procedure and clear prognostic understanding of what will happen with, and without TPIAT.

Molecular Genetics

In 1996, a missense mutation in the cationic trypsinogen gene (PRSS1) was identified in a large hereditary pancreatitis family[22]. Mutations in PRSS1 have since been identified in 65–100% of HP kindreds with an estimated penetrance of 80%. Since this discovery, additional genes associated with recurrent acute and chronic pancreatitis have been identified, particularly SPINK1, CFTR, and CTRC[23–26] (Tables45.1 and45.2). Other important genes that have been associated with chronic pancreatitis include CLDN2, CASR, CTSB, CPA1, GGT1, and TRPV6 [27–29]. Disease mechanisms for many of the genes associated with pancreatitis are complex, and gene–gene and gene–environment interactions are not fully defined.

PRSS1

Cationic trypsinogen is the most abundant isoform of trypsinogen (~65%), followed by anionic trypsinogen (PRSS2, ~30%) and mesotrypsinogen (PRSS3, ~5%)[30]. Trypsinogen is the inactive zymogen of trypsin, a digestive enzyme and regulator of all pancreatic zymogens, except amylase and lipase. The trypsinogen activation peptide maintains the inactive enzyme until it is cleaved by enterokinase or another trypsin, generally in the duodenum. Self-

destruction (autolysis) occurs at p.R122, which is located on the single chain that links the two globular domains of trypsin. Two calcium- binding pockets serve as “on–off ” switches in response to calcium concentrations, inducing distinct conformational changes. Increased calcium concentrations facilitate trypsin activation, whereas reduced calcium levels permit autolysis.

PRSS1 gain of function mutations fall into two categories: (i) premature activation of trypsin in the pancreas; or (ii) resistance to degradation. The importance of PRSS1 mutations is demonstrated in transgenic mice with early-

onset acinar cell injury and dedifferentiation, inflammatory cell infiltration, and progressive pancreatic fibrosis[31]. Many of the less common PRSS1 variants found in patients with pancreatitis do not appear to be gain- of- function mutations. Instead, they may represent coding region variants causing protein misfolding, and triggering an unfolded protein stress response that drives fibrosis in a poorly defined way[32].

Table45.1 Genes associated withpancreatitis.

Gene Chromosome Type of mutation Mechanism

CTRC 1 Loss of function Diminished trypsin degradation in pancreas

CASR 3 Loss of function; Inappropriate

localization

SPINK1 5 Loss of function Diminished trypsin degradation in pancreas

PRSS1 7 Gain of function

Loss of function

TRPV6 7 Loss of function May alter calcium homeostasis in pancreatic acinar cells

CFTR 7 Loss of function Loss of or diminished bicarbonate conductance leads to

CPA1 7 Loss of function Misfolding-

CTSB 8 Unknown / Gain of function Hypothesized to induce premature activation of

CEL 9 Loss of function The CEL- HYB recombination allele originating from a

CLDN2 X Altered regulatory element Unknown; associated with alcoholic CP

CP: chronic pancreatitis.

Elevated pancreatic calcium levels Hypothesized premature activation of trypsin

Premature activation of trypsinogen in pancreas

Misfolding- induced endoplasmic reticulum stress; associated with nonalcoholic, early- onset CP

detainment of trypsinogen in the pancreas

induced endoplasmic reticulum stress;

associated with nonalcoholic, early- onset CP

trypsinogen

crossover between CEL and pseudogene CELP is associated with an increased risk for pancreatitis

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